A systems biology approach was used to identify early gene signatures that predict immune responses in humans vaccinated with the yellow fever vaccine YF-17D. The study found that vaccination induced genes involved in innate immune sensing and type I interferon production. Computational analysis identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4, which correlated with and predicted CD8+ T cell responses with up to 90% accuracy. Another signature, including B cell growth factor TNFRS17, predicted neutralizing antibody responses with up to 100% accuracy. These results highlight the utility of systems biology in predicting vaccine efficacy. The yellow fever vaccine YF-17D is highly effective, having been administered to over 600 million people globally. It was developed in the 1930s by Max Theiler, who attenuated the pathogenic Asibi strain of yellow fever virus. YF-17D induces a broad spectrum of immune responses, including cytotoxic T lymphocytes, a mixed T helper type I-T helper type II profile, and neutralizing antibodies that can persist for up to 30 years. The mechanism of protection is thought to be mediated by neutralizing antibodies, although cytotoxic T cells may also play a role. The study aimed to perform a multivariate analysis of innate immune responses in humans after vaccination with YF-17D to identify innate immune signatures that predict subsequent adaptive immune responses. High-throughput technologies, including gene expression profiling, multiplex analysis of cytokines and chemokines, and multiparameter flow cytometry, were used in combination with computational modeling. The results showed that YF-17D induces a network of antiviral genes, including those involved in interferon-related antiviral responses, viral recognition, and complement activation. The study also evaluated antigen-specific CD8+ T cell responses and neutralizing antibody titers. It found that the magnitude of the CD8+ T cell response was correlated with the magnitude of the response at later time points. The study identified gene signatures that could predict the magnitude of the CD8+ T cell response and neutralizing antibody response. These signatures were validated using two independent classification methods, classification to nearest centroid and discriminant analysis via mixed integer programming. The study demonstrated that systems biology approaches can be used to predict the magnitude of the adaptive immune response and uncover new correlates of vaccine efficacy. The results suggest that such approaches could be used to predict the immunogenicity and protective efficacy of emerging vaccines. The study also highlights the importance of understanding the mechanisms by which YF-17D induces effective immune responses, which could inform the development of new vaccines against other infections.A systems biology approach was used to identify early gene signatures that predict immune responses in humans vaccinated with the yellow fever vaccine YF-17D. The study found that vaccination induced genes involved in innate immune sensing and type I interferon production. Computational analysis identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4, which correlated with and predicted CD8+ T cell responses with up to 90% accuracy. Another signature, including B cell growth factor TNFRS17, predicted neutralizing antibody responses with up to 100% accuracy. These results highlight the utility of systems biology in predicting vaccine efficacy. The yellow fever vaccine YF-17D is highly effective, having been administered to over 600 million people globally. It was developed in the 1930s by Max Theiler, who attenuated the pathogenic Asibi strain of yellow fever virus. YF-17D induces a broad spectrum of immune responses, including cytotoxic T lymphocytes, a mixed T helper type I-T helper type II profile, and neutralizing antibodies that can persist for up to 30 years. The mechanism of protection is thought to be mediated by neutralizing antibodies, although cytotoxic T cells may also play a role. The study aimed to perform a multivariate analysis of innate immune responses in humans after vaccination with YF-17D to identify innate immune signatures that predict subsequent adaptive immune responses. High-throughput technologies, including gene expression profiling, multiplex analysis of cytokines and chemokines, and multiparameter flow cytometry, were used in combination with computational modeling. The results showed that YF-17D induces a network of antiviral genes, including those involved in interferon-related antiviral responses, viral recognition, and complement activation. The study also evaluated antigen-specific CD8+ T cell responses and neutralizing antibody titers. It found that the magnitude of the CD8+ T cell response was correlated with the magnitude of the response at later time points. The study identified gene signatures that could predict the magnitude of the CD8+ T cell response and neutralizing antibody response. These signatures were validated using two independent classification methods, classification to nearest centroid and discriminant analysis via mixed integer programming. The study demonstrated that systems biology approaches can be used to predict the magnitude of the adaptive immune response and uncover new correlates of vaccine efficacy. The results suggest that such approaches could be used to predict the immunogenicity and protective efficacy of emerging vaccines. The study also highlights the importance of understanding the mechanisms by which YF-17D induces effective immune responses, which could inform the development of new vaccines against other infections.